The promising role of tumor-associated macrophages in the treatment of cancer

Wang, Hongbin; Wang, Xueying; Zhang, Xin; Xu, Wanhai

doi:10.1016/j.drup.2023.101041

Cited by 21 publications

(8 citation statements)

References 152 publications

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“…S 4 A, B). Accumulating studies have suggested that TAMs can promote cancer growth and metastasis [ 40 ]. Therefore, TNBC 4 T1 cells and Raw264.7 macrophages were co-cultured in vitro using the Transwell model to simulate their coexistence.…”

Section: Resultsmentioning

confidence: 99%

Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling

Wang,

Li,

Hong

et al. 2024

J Exp Clin Cancer Res

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Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and chemotherapy still serves as the cornerstone treatment functioning by inducing cytotoxic cell death. Notably, emerging evidence suggests that dying cell-released signals may induce cancer progression and metastasis by modulating the surrounding microenvironment. However, the underlying molecular mechanisms and targeting strategies are yet to be explored. Methods Apoptotic TNBC cells induced by paclitaxel or adriamycin treatment were sorted and their released extracellular vesicles (EV-dead) were isolated from the cell supernatants. Chemokine array analysis was conducted to identify the crucial molecules in EV-dead. Zebrafish and mouse xenograft models were used to investigate the effect of EV-dead on TNBC progression in vivo. Results It was demonstrated that EV-dead were phagocytized by macrophages and induced TNBC metastasis by promoting the infiltration of immunosuppressive PD-L1+ TAMs. Chemokine array identified CXCL1 as a crucial component in EV-dead to activate TAM/PD-L1 signaling. CXCL1 knockdown in EV-dead or macrophage depletion significantly inhibited EV-dead-induced TNBC growth and metastasis. Mechanistic investigations revealed that CXCL1EV-dead enhanced TAM/PD-L1 signaling by transcriptionally activating EED-mediated PD-L1 promoter activity. More importantly, TPCA-1 (2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide) was screened as a promising inhibitor targeting CXCL1 signals in EVs to enhance paclitaxel chemosensitivity and limit TNBC metastasis without noticeable toxicities. Conclusions Our results highlight CXCL1EV-dead as a novel dying cell-released signal and provide TPCA-1 as a targeting candidate to improve TNBC prognosis. Graphical abstract

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Section: Resultsmentioning

confidence: 99%

Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling

Wang,

Li,

Hong

et al. 2024

J Exp Clin Cancer Res

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“…Macrophages have increasingly been a subject of interest as targets for disease treatments. A meta-analysis reports more than 25 clinical trials targeting tumor-associated macrophages in a range of different cancer types [57]. In atherosclerosis, reducing macrophage mass within plaques is a promising strategy, as is increasing the numbers of anti-inflammatory macrophages and decreasing pro-inflammatory macrophages in damaged heart tissue after myocardial infarction [18, 58].…”

Section: Discussionmentioning

confidence: 99%

Novel 3-D macrophage spheroid model reveals reciprocal regulation of immunomechanical stress and mechano-immunological response

Burchett,

Siri,

et al. 2024

Preprint

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Purpose: In many diseases, an overabundance of macrophages contributes to adverse outcomes. While numerous studies have compared macrophage phenotype after mechanical stimulation or with varying local stiffness, it is unclear if and how macrophages themselves contribute to mechanical forces in their microenvironment. Methods: Raw 264.7 murine macrophages were embedded in a confining agarose gel, where they proliferated to form spheroids over time. Gels were synthesized at various concentrations to tune the stiffness and treated with various growth supplements to promote macrophage polarization. The spheroids were then analyzed by immunofluorescent staining and qPCR for markers of proliferation, mechanosensory channels, and polarization. Finally, spheroid geometries were used to computationally model the strain generated in the agarose by macrophage spheroid growth. Results: Macrophages form spheroids and generate growth-induced mechanical forces (i.e., solid stress) within confining agarose gels, which can be maintained for at least 16 days in culture. Increasing agarose concentration restricts spheroid expansion, promotes discoid geometries, limits gel deformation, and induces an increase in iNOS expression. LPS stimulation increases spheroid growth, though this effect is reversed with the addition of IFN-γ. Ki67 expression decreases with increasing agarose concentration, in line with the growth measurements. Conclusions: Macrophages alone both respond to and generate solid stress. Understanding how macrophage generation of growth-induced solid stress responds to different environmental conditions will help to inform treatment strategies for the plethora of diseases that involve macrophage accumulation.

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“…M2 macrophages have been implicated in promoting chemoresistance, as activated macrophages with an M2 phenotype can protect cancer cells from the cytotoxic effects of chemotherapy by secreting cytokines that inhibit cell death signaling pathways [ 7 – 10 ]. Conversely, depleting M2 macrophages or inhibiting M2 phenotype polarization contributed to the improvement in therapeutic efficiency [ 9 , 40 – 42 ].…”

Section: Discussionmentioning

confidence: 99%

“…Tumor-associated macrophages (TAMs), also referred to as M2 macrophages, serve as the primary immune cells that infiltrate the tumor [ 7 ]. Numerous studies suggest that M2 macrophages facilitate the initiation and dissemination of tumor cells while also enhancing the tumor cells’ capacity to withstand cytotoxic chemotherapy [ 7 – 10 ]. Targeting TAMs has been demonstrated to suppress tumor progression and decrease chemoresistance [ 9 , 11 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

23-Hydroxybetulinic acid attenuates 5-fluorouracil resistance of colorectal cancer by modulating M2 macrophage polarization via STAT6 signaling

Fan,

Cui,

Chen

et al. 2024

Cancer Immunol Immunother

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Macrophage polarization is closely associated with the inflammatory processes involved in the development and chemoresistance of colorectal cancer (CRC). M2 macrophages, the predominant subtype of tumor-associated macrophages (TAMs) in a wide variety of malignancies, have been demonstrated to promote the resistance of CRC to multiple chemotherapeutic drugs, such as 5-fluorouracil (5-FU). In our study, we investigated the potential of 23-Hydroxybetulinic Acid (23-HBA), a significant active component of Pulsatilla chinensis (P. chinensis), to inhibit the polarization of M2 macrophages induced by IL-4. Our results showed that 23-HBA reduced the expression of M2 specific marker CD206, while downregulating the mRNA levels of M2 related genes (CD206, Arg1, IL-10, and CCL2). Additionally, 23-HBA effectively attenuated the inhibitory effects of the conditioned medium from M2 macrophages on apoptosis in colorectal cancer SW480 cells. Mechanistically, 23-HBA prevented the phosphorylation and nuclear translocation of the STAT6 protein, resulting in the inhibition of IL-10 release in M2 macrophages. Moreover, it interfered with the activation of the IL-10/STAT3/Bcl-2 signaling pathway in SW480 cells, ultimately reducing M2 macrophage-induced resistance to 5-FU. Importantly, depleting STAT6 expression in macrophages abolished the suppressive effect of 23-HBA on M2 macrophage polarization, while also eliminating its ability to decrease M2 macrophage-induced 5-FU resistance in cancer cells. Furthermore, 23-HBA significantly diminished the proportion of M2 macrophages in the tumor tissues of colorectal cancer mice, simultaneously enhancing the anti-cancer efficacy of 5-FU. The findings presented in this study highlight the capacity of 23-HBA to inhibit M2 macrophage polarization, a process that contributes to reduced 5-FU resistance in colorectal cancer.

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The promising role of tumor-associated macrophages in the treatment of cancer

Cited by 21 publications

References 152 publications

Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling

Chemotherapy-elicited extracellular vesicle CXCL1 from dying cells promotes triple-negative breast cancer metastasis by activating TAM/PD-L1 signaling

Novel 3-D macrophage spheroid model reveals reciprocal regulation of immunomechanical stress and mechano-immunological response

23-Hydroxybetulinic acid attenuates 5-fluorouracil resistance of colorectal cancer by modulating M2 macrophage polarization via STAT6 signaling

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